Cocaine abuse and dependence continue to extract considerable personal, health and societal tolls in the U.S. and the world. The cycling progressive nature of this disorder stymies efforts to stay abstinent with relapse oft precipitated by impulsive behavior and craving in the face of exposure to cocaine-associated cues (cue reactivity). Serotonin (5-HT) neurotransmission is a strategic nexus that mechanistically connects these phenotypes. The Translational Addiction Sciences Center (TASC) is comprised of a translational team bridging from molecules to cells to animals to humans with the long-term research goal to definitively reveal the role of 5-HT in addiction neurobiology and to integrate this knowledge into the dominant theoretical constructs of addiction. The central research theme of the TASC is that impulsive action and cue reactivity are mechanistically-linked to disrupted 5-HT signaling through the 5-HT2A receptor (5-HT2AR) and 5-HT2CR localized to prefrontal-striatal-thalamic circuitry. Our premise is that restoration of the 5-HT2AR:5-HT2CR balance will repair corticostriatal deficits and ameliorate relapse. The TASC is led by an experienced, translational team that melds classical and state-of-the-art methodologies, bridging chemistry, cellular biology and pharmacology with human and animal psychopharmacology to address this problem. Project 1 will utilize pharmaco-fMRI, dynamic causal modeling, and human laboratory tasks to demonstrate that 5-HT2R gene variants drive both impulsivity and cue reactivity in cocaine-dependent subjects. Project 2 will employ rodent models to illuminate the 5-HT2AR:5-HT2CR imbalance that drives impulsivity and cue reactivity and to provide the experimental platform to normalize 5-HT2AR:5-HT2CR homeostasis and reduce vulnerability to relapse. Project 3 will design and synthesize bifunctional molecules with targeted actions at 5-HT2R to establish proof-of-concept efficacy against relapse in animal models and to study the unique biology of receptor homo- and heteromers. Synergy will be engendered through the Cellular Biology and Pharmacology Core which will centralize genetic screening in humans, cellular assays In vitro for new ligands, receptor signaling and localization ex vivo and studies of receptor homo- and heteromers. The Administrative Core will centralize, coordinate and facilitate the productive community of the TASC, with particular emphasis on removing barriers to success in translational addiction research, optimizing mentoring experiences, and communicating advances in the TASC and the field to the community at large. The progress of the TASC mission will provides insight Into neural dysfunction in the disordered state of drug dependence and establish that restoration of the 5-HT2AR:5-HT2CR balance with targeted new ligands will repair homeostasis and mitigate deleterious behaviors that promote relapse.